HCL is an indolent B-cell neoplasm. Hairy cells typically coexpress CD11c, CD25 and CD103 antigens in addition to the pan B-cell antigen CD20.1 Patients require treatment for pancytopenia, infections or symptomatic splenomegaly and CDA has emerged as the treatment of choice.2 A single course of CDA produces CR in up to 85% of patients and partial response (PR) in 5–25%.3,4 With longer follow-up, relapses of HCL are common. Goodman et al. reported a 37% relapse rate in 209 patients treated with CDA and had at least seven years of follow-up.5 The RR (CR and PR) after re-treatment with CDA ranges from 60 to 90% but with shorter RD. Bone marrow aplasia, prolonged cytopenias and infections increase with repetitive CDA courses.2 Hairy cells exhibit an especially high CD20 antigen density,6 and the anti-CD20 monoclonal antibody rituximab is considered an attractive treatment option.

We conducted a multicenter phase II trial to investigate rituximab in pre-treated HCL patients of any age who had received at least one previous course of CDA. Diagnosis and assessment of remission was established by morphology including peripheral blood smear and bone marrow examination, supported by a positive tartrate-resistant acid phosphatase (TRAP) stain and characteristic immunophenotyping. Relapse was defined as the reappearance of hairy cells in the bone marrow or as any other new disease manifestations after documented CR. Progressive disease (PD) was defined as >50% increase in the percentage of residual tumor cells, or as >50% increase of residual disease-related organomegaly after documented PR.

Between February 1998 and July 2002, 26 patients were accrued. One patient was not evaluable. Of 25 patients, 24 had classical HCL and one a prolymphocytic sub-type. Pre-treatment consisted of CDA (n=25), splenectomy (n=4), interferon-α (n=9) and alkylating agents (n=2). Nine patients had relapsed and 16 had PD. Patients’ characteristics are summarized in Table 1.

Patients received rituximab 375 mg/m2 weekly x 4 doses using standard infusion guidelines. Re-staging was carried out two months after treatment and then every three months during the first three years and every six months thereafter until relapse. Twenty-four of the 25 patients received all of the four planned infusions. One patient stopped treatment after the first infusion because of a dermal vasculitis. Across all follow-up visits the RR was 80% (20/25 patients; 95% CI: 64.32, 95.68) and the rate of CR was 32% (8/25 patients; 95% CI: 13.71, 50.29). Patients with PD at trial registration had higher RR and CR rates compared to relapsed patients (56% vs. 24% and 24% vs. 8% respectively). The RR depends on the number of previous treatments (Table 2). The median RFS was 27 months (95% CI: 15.90, N/A) (Figure 1). Median follow-up time was 27 months. Eight of the 16 patients who achieved CR or PR had a PD. The median RD was 33.6 months. Seven serious adverse events have been recorded: one patient died of cardiac failure one day after the first infusion of rituximab, one patient developed a grade 3 dermal vasculitis and another patient a grade 4 thrombocytopenia. Two patients experienced a basalioma and one patient a prostate cancer during follow-up. One patient died as a result of gastrointestinal bleeding 12 weeks after treatment termination. Most adverse events were grade 1 and 2 expected infusional events that occurred during the first course of rituximab administration.

Rituximab at 375 mg/m2/week × 4 in previously treated HCL has been studied by others. Hagberg and Lundholm7 reported a RR of 64% and Lauria et al.8 50% in a series of 11 and 10 patients respectively. However, Nieva et al. demonstrated a RR of only 25% in 24 CDA-failed patients using the same dose and schedule of ritux-imab.9 This difference may be due to patient selection. The majority of our patients were less pre-treated, having received only one course of CDA. Recently, Thomas et al. published the results of a phase II trial involving 15 patients with relapsed or refractory HCL, using a regimen of eight weekly doses of rituximab at 375 mg/m2. The overall RR was 80%, with 53% CR.10 The higher CR rate suggests that four weekly doses of rituximab may be inadequate to achieve the optimal response.

In conclusion, rituximab has good activity and is well tolerated in patients with HCL. However, the optimal dose and schedule has to be clarified. The efficacy of rituximab as first line treatment for HCL, as treatment of minimal residual disease or in combination with CDA, should be tested in future trials.